Method for coating a surface of a component

ABSTRACT

The invention relates to a method for coating a surface ( 44 ), in particular a microstructured surface, of a component ( 55 ) comprising different materials, in particular glass and silicon, wherein the surface ( 44 ) is first activated and then coated, wherein an oxidising solution, a basic solution or an acid-oxidising solution is used to activate the surface ( 44 ).

The invention relates to a method for coating a surface, in particular amicro-structured surface, of a component comprising different materials,in particular glass and silicon, wherein the surface is first activatedand then coated, a coated component and a nebuliser having a coatedcomponent.

WO 91/14468 A1 and WO 97/12687 A1 each show a nebuliser which ismarketed in the form of an inhaler under the brand name “Respimat” byBoehringer Ingelheim Pharma GmbH & Co. KG. The nebuliser is used forpropellant-free administration of a metered quantity of a liquidmedicament for inhalation. In the inhaler, liquid medicamentformulations are stored in a reservoir and conveyed through a riser tubeinto a metering chamber from which they are finally expelled through anozzle.

The nozzle has a liquid inlet side and a liquid outlet side. On theliquid inlet side is an opening through which the liquid medicamentcoming from the metering chamber is able to enter the nozzle. On theopposite side, the free end face of the nozzle, the liquid then emergesthrough two nozzle openings which are aligned such that the jets ofliquid emerging from the openings strike one another and are therebynebulised. The nozzle openings are formed in at least two superimposedplates, at least one of which has a microstructure, so that the twoplates firmly attached to one another define on one side a liquid inlet,adjoining which is a channel and/or filter system that opens into thenozzle openings. The two plates with the microstructure and the nozzleopenings are referred to as a uniblock in the context of the Respimattechnology.

A nebuliser of this kind usually delivers formulations based on water orwater/ethanol mixtures and within a short time is able to nebulise asmall amount of the liquid medicament formulation, in thetherapeutically required dose, into an aerosol suitable for therapeuticinhalation. Using the nebuliser it is possible to nebulise quantities ofless than 100 microliters in, for example, one actuation to form anaerosol with an average particle size of less than 20 microns, such thatthe inhalable part of the aerosol already corresponds to thetherapeutically effective amount.

In the nebuliser with Respimat technology the medicament solution isconverted by a high pressure of up to 300 bar into a slowly movingaerosol mist destined for the lungs, which can then be breathed in bythe patient. In rare cases, during the use of the nebuliser, residues ofthe formulation solution may adhere to the nozzle outlets as acontaminant, accumulate thereon and lead to clogging of the nozzleoutlets, which may be accompanied by a deflection of the jets of liquidand a change in the fine particle fraction. Even if this effect is veryrare in a nebuliser of the Respimat technology, there is a need to avoiddeposits for reasons of quality control.

To avoid contamination of an outer surface of the nozzle system or amouthpiece by precipitated liquid with fine particle fractions, DE 10300 983 A1 proposes that the corresponding surfaces should be at leastpartially micro- or nano-structured.

The aim of the invention is to provide a method and a component as wellas a nebuliser comprising a component of the kind described hereinbeforewhich is of self-cleaning design with a thin functionalising coating.

According to the invention the objective is achieved by a method whichuses an oxidising solution, a basic solution or an acid-oxidisingsolution to activate the surface.

Surprisingly, it has been found that the solutions mentioned above canbe used to activate surfaces of two different materials, particularlysilicon and glass, which are joined together to form a monolithiccomponent. In the literature, a special solution is always assigned to aparticular material in order to produce the reactive groups needed forinterface functionalisation, as the activation has to be matched to theparticular substrate and specifically developed for different materials.For example, the activation of the surface of the component is carriedout using a so-called piranha solution, namely the powerfully oxidisingperoxomonosulphuric acid (concentrated sulphuric acid: hydrogen peroxidesolution (30%) in the ratio 7:3), at 70° C. for 20 minutes.Alternatively, RCA cleaning may be used which is normally used for wafercleaning in microelectronics. This uses the following solution:water:ammonia solution (25%):hydrogen peroxide solution (30%), in theratio 5:1:1. The component is exposed to the solution at 75° C. for 20minutes.

Preferably, a cell cleaner is used as the basic solution for activatingthe surface. Preferably the cell or glass cleaner made by Hellma GmbH &Co. KG, of Müllheim, Germany, known under the brand name “ Hellmanexsolution” is used, as an aqueous 2% solution at 70° C. for 2×20 minutesin the ultrasound bath, although the manufacturer advises against theuse of ultrasound in conjunction with their “Hellmanex solution”. TheHellmanex solution ensures activation which is effective on all kinds ofmaterials, particularly silicon and glass, in order to produce reactiveinterfaces.

Expediently, before being activated, the surface is cleaned,particularly with isopropanol and water. The component is immersed inisopropanol for five minutes and in water for five minutes. According toone feature, the surface is treated in a solution of hydrofluoric acidafter cleaning. It is bathed for about 20 minutes in an aqueous 3%hydrofluoric acid solution (HF).

According to a further feature, functional silanes in non-polar, aproticor polar-protic solvents are used to coat the surface. The coating isvery thin and is provided as a monolayer. The component with itsactivated surfaces is immersed for about two hours, in a toluenereaction, in a 0.1 to 1% solution of functional trichlorosilanes ordimethylmonochlorosilanes in dry non-polar, aprotic solvents such astoluene, benzene, carbon tetrachloride, n-alkanes (C₅-C₁₀) or the like.Then the component is dried in a nitrogen current and heat-treated in anoven for about one hour at about 120° C. After the heat-treatment excessand non-covalently bound residues are washed off the component usingtoluene and isopropanol. When the reaction is alcoholic, particularlyisopropanolic, first of all a reaction solution has to be activated inorder to be able to carry out interface functionalisation of thecomponent with its activated surfaces of silicon and glass. A 0.1 to 1%solution of functional triethoxysilanes in 2-propanol/water/hydrochloricacid (HCl) in a ratio of 90 to 98:2 to 10:0.2 to 0.5 is stirred forabout five hours at ambient temperature. Then the component with itsactivated surfaces is immersed in the solution for about two hours.After the component has been taken out of the solution the excesssolution is carefully removed from the component, for example byallowing it to drip onto an absorbent non-woven fabric. Then thecomponent is kept at a controlled 120° C. for about two hours. Anyexcess and non-covalently bound residues are washed off the componentusing isopropanol and water after the heat treatment. The followingcategories of materials are used to coat the surfaces:perfluoroalkylsilanes, alkylsilanes, aminoalkylsilanes, carboxylic acidsilanes, trimethylammonium silanes of different chain lengths,particularly C₄-C₁₈, while the functional silanes used may be reactivetrihalosilanes (R₁—Si—R₃, where R═Cl, Br), monohalodimethylsilanes(R₁—Si(CH3)₂R, where R═Cl, Br) or trialkoxysilanes (R₁—Si—R₃, whereR═methoxy or ethoxy groups).

To ensure satisfactory wetting of the surfaces of the component that areto be coated, in order to coat the surfaces the component isadvantageously treated with ultrasound in the reaction solution. Theultrasound treatment in particular ensures the exchange of the reactionsolution in the capillaries of the component.

The objective is achieved in the component comprising at least twoplates firmly joined together, at least one of which has amicrostructure to form a channel and/or filter system and at least onenozzle opening adjoining it, by the fact that at least the surface ofthe microstructure has a coating which has been applied by the methoddescribed above.

As a result of this, any interaction of components and particles of theformulation expelled through the nozzle opening with the interfaces ofthe component is prevented. The free energy of the surface and hence itswettability is minimised in this area, resulting in a reduction in theimmobilisation of residues of material on the nozzle outlet, i.e. in theimmediate vicinity of the nozzle opening. When the component is used,the residues of material are expelled from the component and the coatedcomponent is self-cleaning, thanks to the use of the monomolecular,covalently bound non-stick coating. The functionalisation can be alteredvariably, depending on the interaction of different ingredients of theformulation with the interfaces of the component and may, for example,have hydrophilic or hydrophobic, positively or negatively charged,oleophillic or oleophobic properties.

One plate expediently consists of silicon while the other plate isglass. The silicon plate is provided with a microstructure, i.e. itcomprises the channel or filter system and the nozzle openings and isadhesively bonded to the plate made of glass.

The component consists of the two plates of glass and silicon firmlyjoined together, while the plate consisting of silicon has one or moremicrostructured channels which connect the inlet side to the outletside. On the outlet side there may be at least one round or non-roundnozzle opening 2-10 μm deep and 5-15 μm wide, the depth preferably being4.5 to 6.5 μm and the length being 7 to 9 μm. In the case of a pluralityof nozzle openings, preferably two, the directions of flow through thenozzles in the component which essentially forms a nozzle body extendparallel to one another or are inclined towards one another in thedirection of the nozzle opening. In a component having at least twonozzle openings on the outlet side, the directions of flow may slopetowards one another at an angle of 20° to 160°, preferably at 60° to150°, more preferably 70° to 100°. The nozzle openings are preferablyarranged at a distance of 10 to 200 μm, more preferably at a distance of10 to 100 μm, particularly preferably 30 to 70 μm. A distance of 50 μmis most preferred. The directions of flow meet accordingly in thevicinity of the nozzle openings. In the interests of simplicity anembodiment will be described hereinafter in which only the silicon plateof the component has relief-like microstructures, but not the plate madeof glass. In other embodiments the situation is exactly the reverse, orboth plates comprise these microstructures. On the silicon plate, a setof channels may be formed on the flat surface in order to create aplurality of filter passages (filter channels) in co-operation with thesubstantially flat surface of the glass plate. Additionally, the siliconplate may have a plenum chamber the ceiling of which is in turn formedby the glass plate. The plenum chamber may be provided in front of orbehind the filter channels. It is also possible to have two such plenumchambers. Another set of channels on the substantially flat surface ofthe silicon plate which is provided after the filter channels forms,together with the glass plate, a set of channels that provide aplurality of nozzle outlet passages. Preferably, the totalcross-sectional area of the nozzle outlets is 25 to 500 μm². The entirecross-sectional area is preferably 30 to 200 μm². In another embodimentthis nozzle construction also has only a single nozzle opening. In otherembodiments of this kind the filter channels and/or the plenum chamberare omitted. Preferably, the filter channels are formed by projectionsarranged in a zig-zag configuration. Thus, for example, at least tworows of the projections form a zig-zag configuration of this kind. Anumber of rows of projections may also be formed, the projections beinglaterally offset from one another in order to form additional rows thatare skewed in relation to these rows, these additional rows mentionedabove then forming the zig-zag configuration. In such embodiments theinlet and outlet may each comprise a longitudinal slot for unfiltered orfiltered fluid, each of the slots being substantially the same width asthe filter and substantially the same height as the projections on theinlet and outlet sides of the filter. The cross-section of the passagesformed by the projections may be perpendicular to the direction of flowof the fluid and may decrease from one row to the next, viewed in thedirection of flow. Also, the projections that are arranged closer to theinlet side of the filter may be larger than the projections that arearranged closer to the outlet side of the filter. In addition, thespacing between the silicon plate and the glass plate may becomenarrower in the region from the inlet side to the outlet side. Thezig-zag configuration which is formed by at least two rows ofprojections has an angle of inclination of preferably 20° to 250°.Further details of this construction of the component can be found in WO94/07607.

Finally, the objective is achieved with a nebuliser for delivering aspecific amount of a fluid, in particular a fluid containing amedicament, as an aerosol, using the component of the kind describedhereinbefore.

It will be understood that the features mentioned above and those to beexplained hereinafter may be used not only in the particularcombinations stated but also in other combinations. The scope of theinvention is defined only by the claims.

The invention is hereinafter described in more detail by means of anembodiment by way of example, by reference to the attached drawings,wherein:

FIG. 1 is a longitudinal section through a nebuliser according to theinvention with a tensioned spring,

FIG. 2 is a longitudinal section through the nebuliser according to FIG.1 with the spring relaxed,

FIG. 3 is a perspective view of a component according to the invention,

FIG. 4 is a front view of the component according to FIG. 3 and

FIG. 5 is a magnified partial representation of the component accordingto FIG. 3.

An upper housing part 51 of the nebuliser comprises a pump housing 52 onthe end of which is mounted a holder 53 for a nebuliser nozzle. In theholder 53 is a recess 54 that widens outs and the component 55 in theform of a nozzle body. A hollow piston fixed in a power take-off flange56 of a locking clamping mechanism projects partly into a cylinder ofthe pump housing 52. At its end the hollow piston 57 carries a valvebody 58. The hollow piston 57 is sealed off by a gasket 59. Inside theupper housing part 51 is a stop 60 of the power take-off flange 56 onwhich a compression spring 68 rests. After the tensioning of thecompression spring 68 a locking member 62 slides between a stop 61 onthe power take-off flange 56 and a support 63 in the upper housing part51. An actuating button 64 is connected to the locking member 62. Theupper housing part 51 ends in a mouthpiece 65 and is closed off by aremovable protective cap 66.

A spring housing 67 with the compression spring 68 is rotatably mountedon the upper housing part 51 by means of snap-fit lugs 69 and a rotarybearing. A lower housing part 70 is pushed over the spring housing 67and inside the spring housing 67 is a storage container 71 for fluid 72which is to be nebulised. The storage container 71 is closed off by astopper 73 through which the hollow piston 57 projects into the storagecontainer 71 and dips its end into the fluid 72, i.e. the supply ofactive substance solution.

A spindle 74 for a mechanical counter (optional) is provided in an outersurface of the spring housing 67. A drive pinion 75 is located at theend of the spindle 74 facing the upper housing part 51. On the spindle74 is a slider 76.

The component 55—a so-called uniblock—comprises two plates 40, 41 firmlyjoined together, of which one plate 40 is made of silicon and has amicrostructure 42 for forming a channel or filter system and an adjacentnozzle opening 43. The silicon plate 40 is firmly attached to the glassplate 41 on the side having the microstructure 42.

At least the surface 44 of the microstructure 42 has a coatingconsisting of functional silanes which prevents any interaction ofingredients and particles of the formulation expelled through the nozzleopening 43 with the interfaces of the component 55. During the use ofthe nebuliser comprising the component 55, the material residues areexpelled from the component 55 and the coated component 55 isself-cleaning thanks to the use of the monomolecular, covalently boundnon-stick coating.

The surfaces 44 of the component 55, particularly the microstructure 42,are first cleaned by dipping the component 5 first into isopropanol forfive minutes and then into water for five minutes. Then the component 55is bathed for about 20 minutes in an aqueous 3% hydrofluoric acidsolution (HF).

The activation of the surface 44 itself is carried out using a cellcleaner, particularly the cell or glass cleaner known by the brand name“Hellmanex solution” and produced by Hellma GmbH & Co. KG, of Müllheim,Germany, as an aqueous 2% solution, at 70° C. for 2×20 minutes in anultrasound bath.

For functionalisation, 1H,1H,2H,2H-perfluorooctyltriethoxysilane isused, for example, which is marketed for example under the brand nameDynasylan by Evonik AG of Düsseldorf. After the component 55 has beenexposed for about two hours to a solution containing the functionalsilane under the effect of ultrasound, the excess solution is allowed todrip off the component 55 and the component is treated for about one totwo hours at 120° C. in an oven. After the heat treatment any excess andnon-covalently bound residues are washed off the component 55 usingisopropanol and water.

The invention claimed is:
 1. A method for preparing a nebulizer, themethod comprising: coating a microstructured surface within a componentcomprising glass and silicon, wherein the component consists of a plateof glass and a plate of silicon firmly joined together and at least oneof the plates has one or more microstructured channels, wherein thesurface is first activated and then coated, characterized in that: anoxidizing solution, a basic solution or an acid-oxidizing solution isused to activate the surface, before the activation the surface iscleaned, and coating the surface comprises: applying a reaction solutionto coat the microstructured channels, the reaction solution comprisingfunctional silanes in non-polar, aprotic or polar-protic solvents, andtreating the microstructured surface with ultrasound during applicationof the reaction solution, wherein the ultrasound treatment causes flowof the reaction solution into the microstructured channels; andincorporating the component into a medical device configured to nebulizea liquid medicament passed through the one or more microstructuredchannels.
 2. The method according to claim 1, characterized in that thecoated component is washed.
 3. The method according to claim 1, whereinthe oxidizing solution which is used for activating the surface is asolution consisting of water, ammonia solution, containing 25% ammonia,and hydrogen peroxide solution, containing 30% hydrogen peroxide, in theratio 5:1:1.
 4. The method according to claim 1, wherein a piranhasolution is used as an acid-oxidizing solution for activating thesurface.
 5. The method according to claim 1, wherein before theactivation the surface is cleaned using isopropanol and water.
 6. Themethod according to claim 1, wherein for coating the surface,perfluoroalkylsilanes or alkylsilanes are used.
 7. The method accordingto claim 6, wherein for coating the surface perfluoroalkl silanes ortrialkoxysilanes are used.
 8. The method according to claim 1, whereinfor coating the surface, trihalosilanes, monohalodimethylsilanes ortrialkoxysilanes are used.
 9. The method according to claim 8, whereindimethylmonochlorosilanes in dry non-polar, aprotic solvents are usedfor coating.
 10. The method according to claim 9, wherein for coatingthe component is immersed in a solution of dimethylmonochlorosilanes andthen dried in a nitrogen current.
 11. The method according to claim 8,wherein a solution of trialkoxysilanes is used for coating.
 12. Themethod according to claim 11, wherein a 0.1 to 1% solution of functionaltriethoxysilanes in 2-ropanol/water/hydrochloric acid is stirred forabout five hours and the component with its activated surfaces is thenimmersed in the solution.
 13. The method according to claim 11, whereinafter the component has been taken out of the solution, the excesssolution is removed from the component by allowing it to drip.
 14. Themethod according to claim 11, wherein the trialkoxysilanes used aretrimethoxysilanes or triethoxysilanes.
 15. The method according to claim1, wherein after the coating the component is heat-treated.
 16. Themethod according to claim 15, wherein after the coating the component isheat-treated for 1 to 2 hours at 120° C.
 17. The method according toclaim 1, wherein the reaction solution forms a coating layer on the oneor more microstructured channels, and wherein the coating layer inhibitsaccumulation of a liquid medicament within the one or moremicrostructured channels.